The beginning of the end: how the Atg1 scaffold nucleates autophagosome biogenesis (237.2)

Abstract

Autophagy is a conserved mechanism that is essential for cell survival in starvation. Moreover, autophagy maintains cellular health by clearing unneeded or harmful materials from cells. Autophagy proceeds by the engulfment of bulk cytosol and organelles by a cup‐shaped double membrane sheet known as the phagophore. The phagophore closes upon itself to form the autophagosome, which delivers its contents to the vacuole or lysosome for degradation. A multiprotein complex consisting of the protein kinase Atg1 together with Atg13, Atg17, Atg29, and Atg31 (ULK1, ATG13, FIP200, and ATG101 in humans) has a pivotal role in the earliest steps of this process. In yeast, the phagophore nucleates from a cluster of 20‐30 nm diameter Atg9‐containing vesicles located at a multiprotein assembly known as the preautophagosomal structure (PAS). We determined the crystal structure of a 2:2:2 complex of the earliest‐acting PAS proteins, Atg17, Atg29, and Atg31, at 3.05 Å resolution. Atg17 is crescent‐shaped with a 10 nm radius of curvature. Dimerization of the Atg17‐Atg31‐Atg29 complex is critical for both PAS formation and autophagy, and each dimer contains two separate and complete crescents. Upon induction of autophagy, Atg17‐Atg31‐Atg29 assembles with Atg1 and Atg13, which in turn initiates the formation of the phagophore. The C‐terminal EAT domain of Atg1 sense membrane curvature, dimerizes, and tethers lipid vesicles. These data suggest a structural mechanism for the organization of Atg9 vesicles into the early phagophore.